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Evasion of Tak1-p38α/β-Stat1/2 non-canonical Activin A signalling leads to aberrant mouse prostate epithelial cell proliferation in vitro and in vivo.

Tgf-β ligands induce cell cycle arrest in a variety of mammalian epithelia, including in the prostate. Genetic deregulation of the downstream canonical Smad-dependent pathway is an early well-studied event in tumorigenesis, yet, in prostate cancer such mutations are rare, leaving unexplained how Tgf-β represses prostate cell proliferation.
Here, we adopted a variety of pharmacological and genetic approaches to dissect the pathways controlling proliferation in mouse prostate organoids.
We found that Egf signalling is a potent proliferative stimulus through the concomitant activation of both Pi3k/Akt and Mapk/Erk pathways. However, the autocrine release of the Tgf-β family ligand Activin A has a dominant role over Egf-induced proliferation by promoting the non-canonical Tak1-p38α/β axis, which leads to Mapkapk2, p16, p21, and Stat1/2 activation and cell-cycle arrest.
Bypass of the proliferation barrier can spontaneously occur upon long-term culture and it is associated to aberrant Activin A signalling and DNA replication stress. Finally, orthotopic transplantation of adapted organoids into immunocompetent hosts, leads to aberrant outgrowth and the emergence of prostatic intraepithelial neoplasia (PIN).
Overall, our experiments unveil how Activin A limits mouse prostate progenitor cells proliferation and provide a rationale for the frequent MAP3K7 (TAK1) and ACVR2A (Activin A type II receptor) deletions observed in human primary prostate cancers (20% in the TCGA 2015 dataset).

Identiferoai:union.ndltd.org:unitn.it/oai:iris.unitn.it:11572/266240
Date12 June 2020
CreatorsFoletto, Veronica
ContributorsFoletto, Veronica, Lunardi, Andrea
PublisherUniversità degli studi di Trento, place:Trento
Source SetsUniversità di Trento
LanguageEnglish
Detected LanguageEnglish
Typeinfo:eu-repo/semantics/doctoralThesis
Rightsinfo:eu-repo/semantics/openAccess
Relationfirstpage:1, lastpage:88, numberofpages:88

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